Bipolar Medications in Children and Adolescents: Mood Stabilizers

Detailed information on mood stabilizers and atypical antipsychotics for treatment of bipolar disorder in children and adolescents.

Children and adolescents with bipolar disorder are treated with medications, although none of these medications, with the sole exception of lithium (in patients as young as 12 years old), have received Food and Drug Administration (FDA) approval for this application. Despite the paucity of data, pediatric treatment guidelines have evolved based on empirically derived plans. The Child Psychiatric Workgroup on Bipolar Disorder established guidelines based on the most up-to-date evidence (Kowatch, 2005). In general, these guidelines involve algorithm-based use of mood stabilizers and atypical antipsychotic agents alone or in various combinations.

Use of mood-stabilizing agents in children and adolescents has some unique considerations. Specifically, adolescents and children generally metabolize more rapidly than adults because of more efficient hepatic functions. Also, adolescents and children have faster renal clearance rates than adults. For example, lithium carbonate has an elimination half-life of 30-36 hours in an elderly patient, 24 hours in an adult, 18 hours in an adolescent, and less than 18 hours in children. Steady states also are achieved earlier in children than in adolescents and earlier in adolescents than in adults. Thus, plasma levels may be drawn and assessed earlier in children and adolescents than in adults.

Some consequences of the efficient metabolizing and clearance systems of young individuals are as follows: (1) peak drug levels may show higher plasma concentrations than anticipated in adults, and (2) trough levels may show lower plasma concentrations than anticipated in adults. Thus, children may require higher doses of medications to attain therapeutic response (measured in mg/kg/d) than adults. Special precautions must be taken when dosing psychiatric medications in the treatment of adolescents and children to achieve therapeutic effect while staying safely below toxic levels.

Although the mood stabilizers have not been established as primary treatment of bipolar disorders in adolescents or children by controlled studies, they are used clinically in this context. Mood stabilizers include lithium carbonate, valproic acid or sodium divalproex, and carbamazepine. These medications still are considered first-line agents in managing bipolar disorders in pediatric patients because case reports and limited studies have suggested that efficacy and safety are sufficiently present to benefit the patient with symptom relief and control.

Lithium carbonate is effective in approximately 60-70% of adolescents and children with bipolar disorder and remains the first line of therapy in many settings. Approximately 15% of children receiving lithium medication have enuresis, primarily nocturnal enuresis. In those who do not respond to lithium, sodium divalproex is generally the next agent of choice. As with adult patients with bipolar disorder, carbamazepine often is considered a third choice, after sodium divalproex and lithium carbonate have been tried at optimal doses for a sufficient length of time. This medication often is tried after an acute or crisis state has been stabilized and adverse effects of either sodium divalproex or lithium carbonate are intolerable.

Lamotrigine has been approved for bipolar maintenance therapy in adults, but data in pediatric patients are lacking. Other antiepileptic medications (eg, gabapentin, oxcarbazepine, topiramate) have had mixed results in adults with bipolar disorder in case reports and studies. However, limited data are available regarding the potential usefulness of these medications in pediatric patients with bipolar disorder, though a benefit may theoretically be possible.

Emerging evidence indicates that atypical antipsychotic agents may be used in pediatric patients with bipolar disorder who presents with or without psychosis. Given the antimanic properties demonstrated in adult and limited adolescent studies, olanzapine (Zyprexa), quetiapine (Seroquel), and risperidone (Risperdal) may be considered first-line alternatives to lithium, valproate, or carbamazepine. Pediatric studies with ziprasidone (Geodon) and aripiprazole (Abilify) are limited at this point; this limitation indicates that these agents should be considered second-line alternatives if first-line mood stabilizers or atypical antipsychotic agents are ineffective or if they result in intolerable adverse effects. Clozapine (Clozaril) may be considered only in treatment-refractory cases given its need for frequent hematologic monitoring due to the risk for agranulocytosis.

An important consideration with atypical antipsychotics is the potential for weight gain and metabolic syndrome. The patient's weight should be measured, and a fasting lipid profile and serum glucose level should be evaluated before these agents are started, and these values should be monitored periodically during treatment. Patients and families should be advised of the need to appropriately manage diet and exercise. Limited data indicate that ziprasidone and aripiprazole may have a low potential for these adverse effects and that they may be considered in patients at high risk because of a family or personal history of metabolic abnormalities. Atypical antipsychotics also pose a potential risk for extrapyramidal symptoms and tardive dyskinesia.

Common adverse effects and special concerns for mood stabilizers are listed in Table 1.

Table 1. Mood Stabilizers: Common Adverse Effects and Special Concerns

While mood stabilizers are first-line agents for patients with bipolar disorder, adjunctive medications often are used to control psychosis, agitation, or irritability and to improve sleep. Commonly, antipsychotics and benzodiazepines are used to reduce these symptoms.

Benzodiazepines and Antidepressants for Treating Bipolar Symptoms

Benzodiazepines, such as clonazepam and lorazepam, generally are avoided, but they may be temporarily useful in restoring sleep or in modulating irritability or agitation not caused by psychosis. Because of the slow-on and slow-off action of clonazepam (Klonopin), the risk of abuse is lower with this drug than with fast-acting benzodiazepines such as lorazepam (Ativan) and alprazolam (Xanax). In the outpatient setting, clonazepam may be preferred because of the efficacy and the lowered risks of abuse by the patient or others. Clonazepam can be dosed in the range of 0.01-0.04 mg/kg/d, and it is often administered once per day at bedtime or twice per day. Lorazepam is dosed to 0.04-0.09 mg/kg/d and administered 3 times per day because of its short half-life.

When a patient with bipolar disorder is having a depressive episode, the use of an antidepressant may be considered after a mood stabilizer or atypical antipsychotic agent has been started and after a therapeutic response or level is achieved. Caution must be exercised in starting an antidepressant in a person with bipolar disorder because it may precipitate mania. An antidepressant with a potentially lowered risk of inducing mania is bupropion (Wellbutrin).

Selective serotonin reuptake inhibitors (SSRIs) may also be used. However, because of the risk of mania, doses should be low and titration should be slow. The only SSRI currently FDA approved for the management of unipolar depression in adolescents is fluoxetine (Prozac). However, this agent should be used carefully in patients with bipolar disorder because of its long half-life and because of its potential to exacerbate manic symptoms when not coadministered with an antimanic or mood-stabilizing agent.

All medications used in pediatric bipolar disorder pose a risk of adverse effects or interactions with other medications. These risks should be clearly discussed with patients and families and weighed against the potential benefits. Medication should be started only after informed consent is obtained.

Drug Category: Mood stabilizers -- Indicated for control of manic episodes occurring in bipolar disorder. Mood stabilizers include lithium carbonate, valproic acid or sodium divalproex, and carbamazepine. These medications are considered first-line agents in managing bipolar disorder in pediatric patients.

Toxicity is closely related to serum levels and can occur at therapeutic doses; caution in hypothyroidism, cardiovascular or renal compromise, and diabetes insipidus; decreased intake of sodium may cause increased lithium levels

Drug Name

Valproic acid (Depakote, Depakene, Depacon) -- Although mechanism of action is not established, activity may be related to increased brain levels of GABA or enhanced GABA action. Valproate also may potentiate postsynaptic GABA responses, affect potassium channel, or have a direct membrane-stabilizing effect.Has proven effectiveness in treating and preventing mania. Classified as a mood stabilizer and can be used alone or in combination with lithium. Useful in treating patients with rapid-cycling bipolar disorders and has been used to treat aggressive or behavioral disorders. A combination of valproic acid and valproate (ie, divalproex [Depakote]) has been effective in treating persons in manic phase, with a success rate of 49%.

Coadministration with cimetidine, salicylates, felbamate, and erythromycin may increase toxicity; rifampin may significantly reduce valproate levels; in pediatric patients, protein binding and metabolism of valproate decrease when taken concomitantly with salicylates; coadministration with carbamazepine may result in variable changes of carbamazepine concentrations; may increase diazepam and ethosuximide toxicity (monitor closely); may increase phenobarbital and phenytoin levels while either one may decrease valproate levels; may displace warfarin from protein-binding sites (monitor coagulation tests); may increase zidovudine levels in patients with HIV

Carbamazepine (Tegretol) -- Effective in patients who have not responded to lithium therapy. Also can act to inhibit seizures induced through the kindling effect, which is thought to occur by way of repeated limbic stimulation. Has been effective in treating patients who have rapid-cycling bipolar disorder or those who have not been responsive to lithium therapy.

Adult Dose

200 mg PO bid (100 mg PO qid if susp)May increase at weekly intervals by no more than 200 mg/d tid/qid (bid with ER) until best response obtained; not to exceed 1600 mg/d

Pediatric Dose

10-20 mg/kg/d PO divided bid (qid with susp)

Contraindications

Documented hypersensitivity; history of bone marrow depression; administration of MAOIs within last 14 d

Interactions

Serum levels may increase significantly within 30 d of danazol coadministration (avoid whenever possible); do not administer concurrently with MAOIs; cimetidine may increase toxicity, especially if taken in first 4 wk of therapy; carbamazepine may decrease primidone and phenobarbital levels (their coadministration may increase carbamazepine levels)

Pregnancy

D - Unsafe in pregnancy

Precautions

Caution with increased intraocular pressure; obtain CBCs and serum-iron baseline prior to treatment, during first 2 mo, and yearly or every other year thereafter; can cause drowsiness, dizziness, and blurred vision; caution while driving or performing other tasks requiring alertness

Drug Name

Risperidone (Risperdal) -- Binds dopamine D2-receptor with 20 times lower affinity than for 5-HT2-receptor. Indicated for short-term (3-wk) treatment of acute mania associated with bipolar disorder. May use alone or combined with lithium or valproate.

Adult Dose

2-3 mg PO qd up to 3 wk; may increase by 1 mg/d at 24-h intervals, not to exceed 6 mg/d